Pinyol, RoserTorrecilla, SaraWang, HuanMontironi, CarlaPiqué Gili, MartaTorres Martín, MiguelWei-Qiang, LeowWilloughby, Catherine E.Ramadori, PierluigiAndreu Oller, CarmenTaik, PatriciaLee, Youngmin A.Moeini, AgrinPeix, JuditFaure-Dupuy, SuzanneRiedl, TobiasSchuehle, SvenjaOliveira, Claudia P.Alves, Venancio A.Boffetta, PaoloLachenmayer, AnjaRoessler, SthephanieMinguez, BeatrizSchirmacher, PeterDufour, Jean-FrançoisThung, Swan N.Reeves, Helen L.Carrilho, Flair J.Chang, CharissaUzilov, Andrew V.Heikenwälder, MathiasSanyal, ArunFriedman, Scott L.Sia, DanielaLlovet i Bayer, Josep Maria2023-06-262023-06-262021-05-130168-8278https://hdl.handle.net/2445/199885Background and aims: Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterising NASH-HCC compared to other HCC aetiologies. Methods: We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n = 53 NASH-HCC; n = 74 NASH) and whole exome sequencing (n = 52 NASH-HCC) data were compared to HCCs of other aetiologies (n = 184). Three NASH-HCC mouse models were analysed by RNA-seq/expression-array (n = 20). Activin A receptor type 2A (ACVR2A) was silenced in HCC cells and proliferation assessed by colorimetric and colony formation assays. Results: Mutational profiling of NASH-HCC tumours revealed TERT promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% vs. 3%, p <0.05). In vitro, ACVR2A silencing prompted a significant increase in cell proliferation in HCC cells. We identified a novel mutational signature (MutSig-NASH-HCC) significantly associated with NASH-HCC (16% vs. 2% in viral/alcohol-HCC, p = 0.03). Tumour mutational burden was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 vs. 0.94 mutations/megabase; p <0.0017). Compared to other aetiologies of HCC, NASH-HCCs were enriched in bile and fatty acid signalling, oxidative stress and inflammation, and presented a higher fraction of Wnt/TGF-β proliferation subclass tumours (42% vs. 26%, p = 0.01) and a lower prevalence of the CTNNB1 subclass. Compared to other aetiologies, NASH-HCC showed a significantly higher prevalence of an immunosuppressive cancer field. In 3 murine models of NASH-HCC, key features of human NASH-HCC were preserved. Conclusions: NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature. Lay summary: The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH) is increasing globally, but its molecular traits are not well characterised. In this study, we uncovered higher rates of ACVR2A mutations (10%) - a potential tumour suppressor - and the presence of a novel mutational signature that characterises NASH-related HCC.34 p.application/pdfengcc-by-nc-nd (c) Elsevier, 2021https://creativecommons.org/licenses/by-nc-nd/4.0/Models animals en la investigacióCàncer de fetgeSíndrome metabòlicaModels molecularsMutació (Biologia)ObesitatAnimal models in researchLiver cancerMetabolic syndromeMolecular modelsMutation (Biology)Obesityinfo:eu-repo/semantics/article7180362023-06-26info:eu-repo/semantics/openAccess924236533992698